The principal goal of this new research program is to design, synthesize, and deliver a series of Pilot-Scale Libraries composed of structurally diverse and unique boronic acids and their derivatives to the NIH Molecular Libraries Small-Molecule Repository (MLSMR). While boronic acids have been reported to act as enzyme inhibitors through mimicking transition states, their use as probes of biological systems has been limited. The recent introduction of the boronic acid Velcade as a proteasome inhibitor approved for treatment of certain cancers has renewed interest in using this unconventional functional group in probe and drug development efforts. Toward this end, the PI has assembled an experienced interdisciplinary team of collaborators, including synthetic, medicinal, and computational chemists to assure these novel compounds possess "lead-like" or "drug-like" properties and cover broad areas of structural space not currently represented in the NIH MLSMR, while at the same time possessing the requisite physicochemical and pharmacokinetic properties to be of value as probes for the exploration of biological systems at the molecular level. The specific synthetic tactics to be employed have their foundation in exciting chemistry being developed in our laboratory concerning the utilization of organotrifluoroborates as protected forms of boronic acids. Organotrifluoroborates have been demonstrated to be resistant to oxidation, acids, bases, nucleophiles, and iminium ion chemistry to which boronic acids have various susceptibilities. This flexibility allows processing of ancillary functional groups incorporated within the organotrifluoroborates, while retaining the valuable boron carbon bonds. In this manner, small, readily available organotrifluoroborates can be elaborated in a highly efficient manner, increasing molecular complexity and diversity in a manner that is incompatible with the boronic acid moiety. Subsequently, the key boronic acid functional group can be unveiled through a simple deprotection protocol of the trifluoroborate. This will facilitate the construction and assembly of carefully designed libraries that have absolutely no precedent in the NIH MLSMR, thus significantly expanding the diversity of small molecules with the potential to be valuable probes for the exploration of biological systems at the molecular level.